Modeling of precipitation of ultra-fine particles by pressure reduction over CO2-expanded liquids

A mathematical model has been developed to describe the process of precipitation of ultrafine particles by pressure reduction over gas (CO₂)-expanded liquids. A rapid pressure reduction over a CO₂-expanded organic solution, from 30–70 to 1 bar at 303 K decreases the solution temperature by 30–80 K in a very short span of time (0.5–1.5 min), which generates a rapid, high, and uniform supersaturation of the dissolved solute in the solution and facilitates precipitation of ultrafine particles. The model developed in this work estimates the supersaturation attained, nucleation and growth rates obtained during the pressure reduction over CO₂-expanded organic solutions, and the particle size distribution of the precipitated particles. Cholesterol has been chosen as a model solute to be precipitated, and acetone has been chosen as a solvent. A new method has been developed for prediction of equilibrium solubility of solute which is affected by a decrease in CO₂ mole fraction as well as a simultaneous decrease in solution temperature during pressure reduction. This method combines the semi-empirical approach of using the partial molar volume fraction of solvent in a CO₂-solvent binary mixture and solid–liquid equilibrium data for a solute–solvent system. Size distributions of the precipitated particles have been calculated assuming primary nucleation (homogeneous as well as heterogeneous nucleation) and diffusion-limited growth kinetics. The predicted mean average particle sizes are then compared with the size of cholesterol particles precipitated by pressure reduction of a CO₂-expanded acetone solution of cholesterol. The particle sizes predicted assuming heterogeneous nucleation are found to be closer to the experimentally observed particle sizes, indicating that the heterogeneous nucleation could be the main mechanism of nucleation, which could occur at the gas–liquid interface of the CO₂ bubbling out of CO₂-expanded solution during pressure reduction.     

Crystallization of silibinin from organic solutions using supercritical and aqueous antisolvents

Silibinin, an anticancer drug, was crystallized from organic solutions using supercritical and aqueous antisolvents. Silibinin was dissolved in acetone and ethanol at concentration range of 0.01–0.04 g/mL, and the drug solutions were placed in contact with two different antisolvents, carbon dioxide and water. The mixing of the drug solutions and antisolvents led to the prompt precipitation of silibinin in a solid crystal form. The experimental variables, such as temperature, solution concentration, mixing rate and solution/antisolvent volume ratio were manipulated. When the experiments were conducted with a supercritical antisolvent, the effects of external additives on the crystal habit were examined. α-d-Glucose penta acetate, triton X-100 and urea were added to the solution at concentration range of 0.001–0.003 g/mL as external additives. The temperature increase of 20 °C induced 25% increase in particle size. As the solution concentration was increased from 0.01 to 0.04 g/mL, the average particle size decreased from 35.5 to 22.0 μm in supercritical antisolvent experiments, while the particle size increased from 8.9 to 30.4 μm in aqueous antisolvent experiments. The use of different kinds of external additives resulted in different modifications of the particle shape and structures.     

Effect of pressure and non-isothermal injection on re-crystallization by CO2 antisolvent: Solubility measurements,simulation of mixing and experiments

This work investigated for the first time a CO₂ antisolvent crystallization (SAS) operating in non-isothermal conditions, i.e. injection of a solution warmer than that of the CO₂ – in order to impose an additional driving for crystallization when CO₂ was not a strong antisolvent. The approach focused on phase equilibria (with a distinctive feature of being modeled by artificial neural network) and 3D-simulation of the mixing (considering both heat and mass transfers) in order to detail the supersaturation profiles in the mixing zone and confronted them to the crystallization results. The effect of pressure was investigated as well. The solubility of a model compound, mefenamic acid (MEFE) was measured in CO₂–acetone at 35 °C/8.5, 10 and 15 MPa, and 10 MPa/25, 35 and 45 °C and further correlated by a neural network to provide an easy-to-handle equation of MEFE concentration. Simulations results showed that supersaturation levels were low (around 2) and that the expanding jet spread similarly whatever the pressure. The effect of differential temperature on the mixing behavior and supersaturation was investigated. Compared to isothermal cases, higher superaturations were obtained but only if a more concentrated solution allowed by the higher temperature was processed as well. The benefit for the crystal size was difficult to evidence because of the long sizes of the needles and the difficulties of processing almost saturated solutions. Investigation of a less CO₂–acetone compound would be more promising.     

Polymethylmethacrylate (PMMA) sub-microparticles produced by Supercritical Assisted Injection in a Liquid Antisolvent

A recently developed supercritical assisted process, called Supercritical Assisted Injection in a Liquid Antisolvent (SAILA) is proposed to produce polymer micro and nanoparticles in water stabilized suspensions. Polymethylmethacrylate (PMMA) has been selected as the model polymer for a systematic study of the influence of the SAILA operating parameters on particle morphology and diameter. The effect of expanded liquid injection pressure on particle size and distribution was studied and different expanded liquid temperatures and compositions were also explored. Successful precipitation of the polymer in a water stabilized suspension was obtained and narrow particle size distributions were obtained using 70 and 90 bar injection pressures. PMMA particles controlled diameter were produced ranging between 0.2 ± 0.04 μm and 0.9 ± 0.2 μm. Particles are formed from the expanded liquid solution as a consequence of very fast supersaturation produced by spraying it the liquid antisolvent.     

Precipitation kinetics of PMMA sub-micrometric particles with a supercritical assisted-atomization process

Sub-micrometric particles of PMMA were successfully prepared via a supercritical assisted-atomization (SAA) process using acetone as a solvent and supercritical carbon dioxide as a spraying medium. The effects of several key factors on the particle size were investigated. These factors included the concentration of polymer solution, temperature in saturator and volumetric flow rate ratio of carbon dioxide to polymer solution. The shape of the polymer's primary particles is spherical with the arithmetic mean size ranging from 82 nm to 176 nm and the mass-weighted mean size ranging from 127 nm to 300 nm. As evidenced from the experimental results, the lower concentrations of polymer solution, optimized volumetric flow rate ratios, and higher temperatures in saturator can effectively reduce the mean particle size. The precipitation kinetic parameters were determined from the particle size distributions with the aid of the population balance theory. This study found the primary nucleation to be dominant in the precipitation and diffusion may govern particle growth.     

Kinetics modeling of ampicillin nanoparticles synthesis via supercritical gas antisolvent process

Modeling of supercritical gas antisolvent (GAS) process was carried out for ampicillin nanoparticles synthesis. The particle size distribution of ampicillin limits bioavailability. Therefore, the kinetic data are essential for the control of particle size. Volume expansion and phase equilibrium modeling was studied to determine optimal operating conditions for experimental ampicillin production. Experimental ampicillin precipitations with GAS process at various antisolvent addition flow rates were investigated. The process model was then studied for the determination of nucleation and growth rate parameters. Equation of state, material and population balance equations were used for this modeling. A combination of the Crank-Nicholson and Lax-Wendroff methods was utilized to solve the population balance equation. Comparison of the experimental and modeling data showed that the model successfully predicted the particle size distribution. The effect of antisolvent addition rate on nucleation indicated that nucleation was enhanced via higher antisolvent addition rate and consequently smaller particle size was obtained. The mean particle sizes of ampicillin were obtained to be 357.09, 337.04 and 356.68 nm at antisolvent flow rates of 1.6, 2 and 2.4 mL/min, respectively.     

Synthesis of 5-Fluorouracil nanoparticles via supercritical gas antisolvent process

The micronization of an anticancer compound (5-Fluorouracil) by supercritical gas antisolvent (GAS) process was investigated. 5-Fluorouracil was dissolved in dimethyl sulfoxide (DMSO) and subsequently carbon dioxide as an antisolvent was injected into this solution thus, the solution was supersaturated and nanoparticles were precipitated. The influence of antisolvent flow rate (1.6, 2 and 2.4 mL/min), temperature (34, 40 and 46), solute concentration (20, 60 and 100 mg/mL) and pressure (9, 12 and 15 MPa) on particle size and particle size distribution were studied. Particle analyses were performed by scanning electron microscopy (SEM) and Zetasizer Nano ZS. The mean particle size of 5-Fluorouracil was obtained in the range of 260–600 nm by varying the GAS effective parameters. The High performance liquid chromatography (HPLC) and Fourier transforms infrared spectroscopy (FTIR) analyses indicated that the 5-Fluorouracil nanoparticles were pure and the nature of the component did not change. The experimental results indicated that increasing the antisolvent flow rate and pressure, while decreasing the temperature and initial solute concentration, led to a decrease in 5-Fluorouracil particle size.     

Nucleation Rate Prediction of Curcumin Particles in Microfluidic‐Assisted Nanoprecipitation

A hybrid computational model was developed to interpret the formation of curcumin particles via liquid antisolvent precipitation (LASP) in three microchannel reactors (MCRs) with different confluence angles. The computational fluid dynamics (CFD) model was numerically combined with a discretized population balance approach. The nucleation kinetics were computed using an expression obtained from the nucleation rate and supersaturation equation from previous experimental data. A quantitative comparison of the particle size distributions (PSDs) demonstrated that the particles with the smallest diameters are observed right after the intersection of the three streams. Besides, the large confluence angle of 135° in the MCR presented higher population density as a result of the smaller size of the precipitated curcumin particles. These findings illustrate the efficient applicability of the hybrid model.     

Processing naproxen with supercritical CO2

Naproxen has been processed with supercritical fluids in order to improve the dissolution rate and bioavailability. Microparticles of naproxen have been obtained by a Rapid Expansion of Supercritical Solutions (RESS) process in which carbon dioxide has been used as a solvent and methanol as a cosolvent. The influence of extraction pressure (200–300 bar) and extraction temperature (60 °C and 100 °C) on the naproxen precipitation has also been investigated. In general, the morphology of the precipitated particles improved and particle size (PS) decreased in comparison to the raw material. Lower extraction pressure and higher extraction temperature led to a smaller particle size. On the other hand, a supercritical antisolvent (SAS) process has been applied due to the relative medium solubility values of naproxen in supercritical carbon dioxide, with precipitation obtained successfully in all cases. The initial concentration of the solution and the solvent effect has both been analysed. Morphologies and mean diameter ranges have been analysed by scanning electron microscopy (SEM) and the influence on crystallinity of both supercritical processes has been evaluated by X-ray diffraction (XRD) measurements.     

Numerical simulation of particle formation in the rapid expansion of supercritical solution process

In this paper, we numerically study particle formation in the rapid expansion of supercritical solution (RESS) process in a two dimensional, axisymmetric geometry, for a benzoic acid + CO₂ system. The fluid is described by the classical Navier–Stokes equation, with the thermodynamic pressure being replaced by a generalized pressure tensor. Homogenous particle nucleation, transport, condensation and coagulation are described by a general dynamic equation, which is solved using the method of moments. The results show that the maximal nucleation rate and number density occurs near the nozzle exit, and particle precipitation inside the nozzle might not be ignored. Particles grow mainly across the shocks. Fluid in the shear layer of the jet shows a relatively low temperature, high nucleation rate, and carries particles with small sizes. On the plate, particles within the jet have smaller average size and higher geometric mean, while particles outside the jet shows a larger average size and a lower geometric mean. Increasing the preexpansion temperature will increase both the average particle size and standard deviation. The preexpansion pressure does not show a monotonic dependency with the average particle size. Increasing the distance between the plate and the nozzle exit might decrease the particle size. For all the cases in this paper, the average particle size on the plate is on the order of tens of nanometers.     

Dense CO2 antisolvent precipitation of levothyroxine sodium: A comparative study of GAS and ARISE techniques based on morphology and particle size distributions

Morphology and particle size distribution of levothyroxine sodium are experimentally investigated by comparing gas antisolvent (GAS) and atomized rapid injection for solvent extraction (ARISE) techniques using dense CO₂. Precipitation of levothyroxine sodium from ethanol was carried out at 25, 40 and 50 °C, with pressure in the 90–120 bar range and different concentrations of the organic solution. Particles produced by the GAS process are nanospheres whereas ARISE processed particles are either spherical or rod-like micro and nanoparticles. Particle size and size distributions of GAS processed levothyroxine sodium are in the 370–500 nm range, while the ARISE process produced particles in the 360–1200 nm range. In most cases, both techniques produced bimodal size distributions, due to particle agglomeration. The different morphological characteristics and particle size distributions of levothyroxine sodium obtained using GAS and ARISE at different operating conditions can be useful depending on the type of drug formulation chosen, as well as the route of drug administration and delivery system.     

Generation and precipitation of paclitaxel nanoparticles in basil seed mucilage via combination of supercritical gas antisolvent and phase inversion techniques

In recent years, plant derived polymers have evoked tremendous interest in the field of drug delivery. In this work, a promising anticancer drug, paclitaxel, was precipitated in the basil seeds mucilage (BSM) using supercritical carbon dioxide (SC-CO₂). The employed SC-CO₂ process in this research is a combination of gas antisolvent and phase inversion techniques and consists of two steps: (1) casting solution preparation, a uniform mixture of BSM, water, paclitaxel and dimethyl sulfoxide (DMSO), (2) simultaneous generation and precipitation of nanoparticles in BSM structure using SC-CO₂ as antisolvent. The effect of DMSO/water ratio (4 and 6 (v/v)), pressure (10–16 MPa) and CO₂ addition rate (1–3 mL/min) on mean particle size (MPS), particle size distribution (PSD) and drug loading efficiency (DLE) were studied. Particle analyses were performed by scanning electron microscopy (SEM) and Zetasizer. High performance liquid chromatography was utilized for studying DLE. Nanoparticles of paclitaxel (MPS of 117–200 nm depending on process variables) with narrow PSD were successfully precipitated in BSM structure with DLE of 56.8–78.2%. The FTIR spectra confirmed that paclitaxel actually precipitated in basil seeds mucilage. Experimental results indicated that higher DMSO/water ratio, pressure and CO₂ addition decreased MPS and DLE.     

Encapsulation of nanoparticles using CO2-expanded liquids

A new process for encapsulation based on the principle of precipitation of nanoparticles by pressure reduction of CO₂ gas-expanded liquids (PPRGEL) is presented here. Encapsulation has been studied for two types of core solid nanoparticles, namely suspended and in situ produced particles from solution. Mechanisms for both types of encapsulations have been proposed: for the former type deposition happens because of mass transfer from the bulk solution; for the latter type encapsulation happens if the supersaturation profiles of the core and coating solutes are staggered in time in order that the core solute precipitates first and the coating solute deposits on it by mass transfer. A model for the process that includes nucleation and growth has been developed to select systems and process conditions that favor encapsulation. The mechanisms have been experimentally verified at 52 bar and 303 K for (i) encapsulation of suspended nanoparticles of silica with ascorbylpalmitate (AP) dissolved acetone and (ii) encapsulation of in situ produced tartaric acid (TA) nanoparticles with AP, both initially dissolved in acetone. A uniform coating of about 10–20 nm of AP is formed on the 250 nm silica particles. For the two-solute system it is observed that AP deposits on TA resulting in encapsulated particles of an average size of about 520 nm.     

Manipulating the size,the morphology and the polymorphism of acetaminophen using supercritical antisolvent (SAS) precipitation

The supercritical antisolvent technology is used to crystallize paracetamol particles. Supercritical carbon dioxide (scCO₂) is used as antisolvent. Ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of paracetamol in the solution was varied between 1 and 5 wt%, the composition of the ethanol/acetone solvent mixture between 50 and 90 wt% of ethanol and the operation pressure between 10 and 16 MPa at a temperature of 313 K. The most important finding is that the polymorph of paracetamol crystals can be adjusted between monoclinic and orthorhombic by varying the content of ethanol in the solution. The second important finding is that the occurrence of primary and secondary crystal structures can be explained solely by the overall supersaturation during the crystallization process. While X-ray diffraction was used to analyze the polymorph of the particles, their morphology was analyzed using scanning electron microscopy.     

Laser analyses of mixture formation and the influence of solute on particle precipitation in the SAS process

Laser based Raman and elastic light scattering measurements were performed to study the process of mixture formation and the influence of the solute paracetamol onto the phase behaviour of the pseudo-binary system ethanol/CO₂ in the supercritical antisolvent process. From the Raman based technique, mole fraction and partial density distributions of CO₂ were obtained. The mole fraction distributions indicate a rapid mixture formation with fast supersaturation of the solute. At the same time, the increase of the CO₂ partial density at conditions considerably above the mixture critical point (MCP) indicate a change from a homogeneous supercritical to a multi-phase subcritical flow. This phase change goes along with particle precipitation. Thus, the results of our investigations proof, why past approaches failed to generate amorphous paracetamol nanoparticles with the system paracetamol/ethanol/CO₂ above the MCP. Process parameters like injection pressure (20.0–35.0 MPa), chamber pressure of CO₂ (7.5–17.5 MPa), temperature (313–333 K) and solute concentration (0–5 wt%) were varied.     

Evidence for sub-3 nanometer neutralized particle detection using glycerol as a condensing fluid

A two-step condensation process was utilized, with glycerol introduced via an initial precondenser step, with secondary condensation and detection occurring within a traditional n-butanol operated condensation nucleus counter. Experimental results suggested that the size-threshold for detection by condensation nucleation was decreased by using glycerol versus n-butanol. Based on the predictions from particle size distributions, the smallest particles that could be detected were estimated to have diameters somewhere in the 0.55–1.7 nm range. Potential interferences due to incomplete droplet desolvation or penetration loss differences were predicted to have negligible impact on this estimation. A direct comparison of the capability of the precondenser system and the TSI UCPC 3025A to detect small particles was made, showing that the precondenser system could detect smaller particles (estimated as having diameters as small as 1.6–1.7 nm) than the UCPC 3025A when both systems were compared close to conditions of critical supersaturation in the respective condensers.     

Experimental investigation on the micronization of aqueous cefadroxil by supercritical fluid technology

The supercritical-assisted atomization (SAA) process is a novel technique proposed recently to prepare micro-particles with controlled particles size distribution suitable for aerosolizable delivery. It has shown a great potential in drug micronization especially for water-soluble drugs. Cefadroxil micro-particles were prepared successfully from water–ethanol mix-solvent by SAA process. The influence of the operation parameters, including the pressure and temperature in the mixing vessel, the solution concentration and the solution feed rate, on the particle morphology, size and size distribution was investigated in detail. The results show that the concave cefadroxil micro-particles suitable for pulmonary drug delivery could be prepared by SAA process in certain conditions. The pressure in the mixing vessel and the solution feed rate are two most effective parameters while the solution concentration is the next. The temperature in the mixing vessel has a little effect. The particle characteristics could be controlled by adjusting operation conditions. The optimal operation parameters for preparing cefadroxil micro-particles in the scope of this work are: the pressure of 10 MPa and the temperature of 60 °C in the mixing vessel, the solution feed rate of 3 ml/min, and the solution concentration of 4 mg/ml.     

TiC whisker reinforced ultra-fine TiC-based cermets: Microstructure and mechanical properties

TiC whisker reinforced ultra-fine TiC-based cermets were fabricated and their microstructures as well as mechanical properties were characterized and compared with microsized and ultra-fine cermets. The effects of high energy milling and subsequent annealing on the composition and microstructure of microsized TiC powders were studied. It was shown that the particle size distribution of TiC powders played a critical role in determining cermets׳ microstructure and properties. Inverse grain (White core with grey rim) only exists in ultra-fine cermet with a narrow size distribution of annealed TiC powders. Large discrepancy of larger TiC powders (microsized particles or whiskers) and ultra-fine particles in size resulted in a bimodal grain size feature. Additionally, mechanical property testing was conducted and was related to the microstructural features. The whisker reinforced cermets own much higher toughness of 12.43 Mpa m^1/2 than the microsized and ultra-fine cermets, with a hardness (Hv₃₀, 1620) between them.     

Interactions of phase equilibria,jet fluid dynamics and mass transfer during supercritical antisolvent micronization

Supercritical antisolvent (SAS) precipitation has been successfully used in the micronization of several compounds. Nevertheless, the role of high-pressure vapor–liquid equilibria, jet fluid dynamics and mass transfer in determining particle size and morphology is still debated. In this work, CO₂ has been adopted as supercritical antisolvent and elastic light has been used to acquire information on jet fluid dynamics using thin wall injectors for the investigation of the liquid solvents acetone and DMSO at operating conditions of 40 °C in the pressure range between 6 and 16 MPa. The results show that two-phase mixing after jet break-up is the phenomenon that characterizes the jet fluid dynamics at subcritical conditions. When SAS is performed at supercritical conditions a transition between multi-phase and single-phase mixing is observed by increasing the operating pressure. Single-phase mixing is due to the very fast disappearance of the interfacial tension between the liquid solvent and the fluid phase in the precipitator. The transition between these two phenomena depends on the operating pressure, but also on the viscosity and the surface tension of the solvent. Indeed, single-phase mixing has been observed for acetone very near the mixture critical point, whereas DMSO showed a progressive transition for pressures of about 12 MPa.In the second part of the work, a solute was added to DMSO to study the morphology of the microparticles formed during SAS precipitation at the different process conditions, to find a correlation between particle morphology and the observed jet. Expanded microparticles were obtained working at subcritical conditions; whereas spherical microparticles were obtained operating at supercritical conditions up to the pressure where the transition between multi- and single-phase mixing was observed. Nanoparticles were obtained operating far above the mixture critical pressure. The observed particle morphologies have been explained considering the interplay among high-pressure phase equilibria, fluid dynamics and mass transfer during the precipitation process.     

Micronization of ketoprofen by the rapid expansion of supercritical solution process

The particle size of the pharmaceutical substances is important for their bioavailability (the percentage of the drug absorbed compared to its initial dosage). The absorption rate can be increased by reducing particle size of the drug particles. This study was conducted to investigate the effects of the extraction pressure (140–220 bar), extraction temperature (308–338 K), nozzle length (2–15 mm), effective nozzle diameter (450–1700 μm), and collection distance (1–10 cm) on the size and morphology of the precipitated ketoprofen particles. The characterization (size and morphology) of the particles was investigated using scanning electron microscopy (SEM). The average particle size of the original material was 115.42 μm, while the average particle size of the micronized particles is between 0.35 and 7.03 μm near to quisi-spherical, needle and irregular shape depending upon the experimental conditions.